1. Field of the Invention
The present invention relates generally to cancer therapy and, more particularly, to the potentiation or enhancement of cytotoxic conjugates of monoclonal antibodies (MoAbs) and ribosomal inhibiting proteins (RIPs) by the co-administration of a second, unconjugated monoclonal antibody.
Colorectal cancer is the second most common cause of death from malignancy in the Western world. The American Cancer Society estimates that there were 138,000 new cases of colorectal cancer and 59,900 patients died from the disease in 1985. The outlook for patients with colorectal disease has remained essentially unaltered over the last 30 years, with the five-year survival being on the order of 30%. A major factor contributing to this is the lack of effective treatment for the disease once it has spread beyond the bowel wall, since surgery during the early stages of the disease offers the only prospect of cure.
Unfortunately, the majority of patients have disseminated disease at the time of initial surgery, primarily with overt or occult hepatic and lymph node metastases.
Despite numerous trials of chemotherapy, the only single agent shown to have any significant effect is 5-fluorouracil; its response rate is inadequate and treatment with it rarely influences the ultimate outcome. Combination chemotherapy and intrahepatic arterial infusion are being investigated but currently do not represent effective treatments.
Cancer of the ovary accounts for roughly 5% of all cancers in women and is the sixth leading cancer in women. Although surgery is curative if this lesion is detected early enough, the mortality associated with this disease has not improved appreciably in the last 25 years.
Ultrasound, laparoscopy or peritoneoscopy, and CAT scan are of limited value in the diagnosis of ovarian carcinoma. Serum markers such as carcinoembryonic antigen and placental alkaline phosphatase as well as some newly defined antigens are found in the blood of some patients with adenocarcinoma, although there is no universal marker. Surgery with biopsy is the only definitive way of diagnosing ovarian carcinoma.
Surgery is currently the only cure for ovarian carcinoma, and is only curative if the tumor has not spread. Radioisotope implants, x-ray irradiation, and chemotherapy are of limited use in the management of ovarian carcinoma.
The most important prognostic indication is the extent of spread of the tumor at the time of diagnosis and surgery. Stage I ovarian carcinoma (growth limited to the ovaries) has an overall 5-year survival rate of approximately 80% Stage II (growth involving ovaries with pelvic extension) has a 5-year survival rate of 40%, Stage III (growth involving ovaries with extension to small bowel or omentum) has a 5-year survival rate of 10%, and Stage IV (distant metastases) has a 5-year survival rate of less than 5%. The relative 5-year survival rate for ovarian carcinoma is 37% (1973-80), relatively the same as for 1960-63 (32%).
Imaging studies of ovarian carcinoma with radiolabelled MoAbs have been performed to a limited degree in human and animal systems. Tumors as small as 1 mm in diameter in mice bearing xenografts of human ovarian cancer have been imaged. The same study also detected tumors in 8 of 10 patients with ovarian cancer.
Osteogenic sarcoma (OS) is the most common primary bone tumor. Although surgery can be curative if this lesion is detected early enough, the usual course of this disease in 80%-85% of patients is multiple pulmonary metastases and death within two years of diagnosis. These metastases are often present but usually not large enough to be seen at diagnosis of the primary tumor.
Amputation is the treatment of choice for OS. Limb salvage procedures have been performed, such as en-block resection and prosthetic replacement. Overall survival for limb salvage is either as poor as worse than with amputation.
Radiation treatment has not been shown to prevent OS metastases.
Most recent trials note survival rates of over 50% at 5 years for patients treated by widely diverse adjunctive methods. The question is whether all of these widely diverse forms of treatment are effective or if there is a change in the natural history of the disease.
Imaging studies of OS with radiolabelled MoAbs have been performed to a limited degree in human and animal systems. Human OS xenografts have been imaged in nude mice using an anti-OS MoAb labelled with .sup.131 I.
Because of the extent of these three forms of cancer, there is a need for new compositions and methods to treat primary, recurrent and metastatic disease.
2. Description of the Relevant Literature
Embleton et al., Br. J. Cancer (1981) 43:582-7, report preparation of a hybridoma against osteogenic sarcoma cell line 791T, and binding properties of the resulting MoAb with respect to a variety of cell types.
Farrands et al., Lancet (1982) 2:397-400, describe radioimaging of human colorectal cancers using MoAb 791T radiolabelled with .sup.131 I.
Pimm et al., Int. J. Cancer (1982) 30:75-85, describe in vitro localization of osteogenic sarcoma xenografts in mice using radiolabelled 791T MoAbs.
Price et al., Br. J. Cancer (1982) 46:610-10, report on complement-dependent cytotoxicity of two anti-791T osteogenic sarcoma MoAbs against human tumor cell lines, and failure of one of these MoAbs to inhibit 791T tumor xenografts in mice.
Embleton et al., Br. J. Cancer (1983) 47:43-9, describe coupling of the drug vindesine to 791T MoAbs, and in vitro cytotoxicity testing of the conjugate.
Garnette, et al., Int. J. Cancer (1983) 31:661-70, describe in vitro cytotoxicity testing of a 791T MoAb methotrexate conjugate.
Baldwin, et al., Bull.Cancer (1983) 70:132-6, describe the use of radiolabelled 791T MoAb to detect colorectal carcinoma, and evaluate the MoAb for targeting anti-tumor agents including cytotoxic drugs and immunomodulating agents.
Pelham, et al., Cancer Immunol. Immunother. (1983) 15:210-6, describe coupling of interferon to the MoAb 791T, and the retention of biologic activity if both entities of the conjugate.
Baldwin and Pimm. Cancer Metastasis Rev. (1983) 2:89-106, summarize a series of radioimaging experiments using .sup.131 I labelled 791T MoAbs to localize human tumor xenografts in mice.
Farrands et al., J. Bone Joint Surg. (1983) 65:638-4, report on detection of a primary osteogenic sarcoma in a patient using .sup.131 I labelled 791T MoAbs.
Price et al., Scand. J. Immunol. (1983) 18:411-20, report on the identification of an antigen on mitogen-stimulated peripheral blood mononuclear cells using the MoAb 791T, and the characterization of this antigen as being identical to the 791T MoAb-defined antigen found on osteogenic sarcoma cells.
Embleton et al., Br. J. Cancer (1984) 49:559-65, describe treatment of osteogenic sarcoma cells with a methotrexate/791T MoAb conjugate at toxic concentrations which allowed "escape" of some tumor colonies, which were then evaluated for growth potential.
Armitage et al., Br. J. Surg (1984) 71:407-12, report on the imaging of gastrointestinal cancers in patients and discuss radiolabelled 791T MoAb uptake in malignant and non-malignant tissue.
Pimm and Baldwin, Eur J. Cancer Clin. Oncol. (9184) 20:515-24, describe the extent and rate of localization of radiolabelled 791T MoAb in osteogenic sarcoma xenografts in mice.
Price et al., FEBS Lett. (1984) 171:31-5, report on the characterization of the cell surface antigen p72 with which the MoAb 791T reacts.
Price et al., Br. J. Cancer (1984) 49:809-12, review radioimaging studies using 791T and discuss localization of the antibody within the tumor.
Gallego et al., Int. J. Cancer (1984) 33:737-44, report on the coupling of the drug daunomycin to the MoAb 791T, using four different coupling procedures, and evaluate the four conjugates for cytotoxicity to tumor cells.
Flannery et al., Eur. J. Cancer Clin. Oncol. (1984) 20:791-8, describe coupling of interferon to the MoAb 791T, and the activation of NK cells by this conjugate.
Campbell et al., Int. J. Cancer (1984) 34:31-7, describe the analysis of expression on various cell lines of the antigen with which the MoAb 791T reacts.
Baldwin et al., Symp. Fundam. Cancer Res. (1983) 36:437-55, describe radioimaging of primary and metastatic colorectal carcinomas in patients using radiolabelled 791T MoAb.
Embleton et al., Behring Inst. Mitt. (1984) 74:108-11, summarize cytotoxicity testing of a vindesine/791T MoAb conjugate and a methotrexate/791T MoAb conjugate.
Embleton et al., Behring Inst. Mitt. (1984) 74:35-8, summarize reactivity of two anti-human tumor MoAbs, 791T and C14/1/46.
Pimm et al., Behring Inst. Mitt. (1984) 74:80-6, describe detection of primary and metastatic colorectal carcinoma in patients using .sup.131 I labelled 791T MoAb.
Williams et al., Clin. Oncol. (1984) 10:375-81, describe detection of primary and metastatic mammary carcinoma in patients using .sup.131 I labelled 791T MoAb.
Symonds et al., Br. J. Obstet Gynaecol. (1985) 92:270-6, describe preliminary results of detection of ovarian tumors in patients using .sup.131 I labelled 791T MoAb.
Rowland et al., Cancer Immunol. Immunother. (1985) 19:1, report formation of four vindesine-MoAb conjugates, including the MoAb 791T, and compare the conjugates, free vindesine, and free MoAb for their ability to inhibit tumor cell growth.
Pimm et al., Cancer Immunol. Immunothen. (1985) 19:18-21, describe localization of a primary osteogenic sarcoma tumor in situ using .sup.131 I-labelled 791T MoAb, and subsequent localization of xenografts of the tumor in mice.
Perkins et al., Eur. J. Nucl. Med. (1985) 10:296-301, report on a method of labelling the MoAb 791T with .sup.111 In.
Pimm et al., J. Nucl. Med. (1985) 26:1011-23, describe characteristics of the blood survival of .sup.131 I and .sup.111 In-labelled 791T MoAbs in patients with colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma in tumor imaging studies.
Pimm et al, Eur. J. Nucl. Med. (1985) 11:300-4, describe comparison of the blood, tumor and wholebody levels of .sup.131 I and .sup.111 In labelled 791T MoAb in mice with human tumor xenografts.
Pimm et al., ICRS Med. Sci. (1985) 13:499-500, describe the production of anti-idiotypic antibodies to 791T MoAb following administration of radiolabelled 791T MoAb in a series of patients.
Pimm et al., ICRS Med. Sci. (1985) 13:366-7, describe a solid-phase micro-radioimmunoassay as a means of measuring MoAb reactivity with antigens, using 791T as an example.
Armitage et al., Nucl. Med. Commun. (1985) 6:623-31, describe imaging of primary and metastatic colorectal carcinoma using .sup.111 In labelled 791T MoAb.
Durrant et al., Br. J. Cancer (1986) 53:37-45, report on the localization of the MoAb 791T within xenografts derived from colorectal adenocarcinomas.
Garnett and Baldwin, Cancer Res. (1986) 46:2407-12 describe improved synthesis of a drugcarrier-MoAb conjugate using methotrexate and 791T.
Ramakrishnan and Houston, Science (1984) 223:58-61, describe the potentiation of immunotoxins directed against human acute lymphoblastic leukemia by chloroquine.
Akiyama et al., Cancer Res. (1985) 45:1005-07, report the potentiation of the cytotoxic activity against human tumor cells of toxic conjugates of Pseudomonas exotoxin with anti-transferrin receptor antibody or epidermal growth factor up to 10 to 20 fold by the calcium antagonists verapamil, D-600, and diltiazem and by the lysosomotropic agent .beta.-glycylphenylnaphthylamide.
Uckun et al., Blut (1985) 50:19-23 describe the potentiation by mafosfamid (ASTA Z 7557) of the ex vivo efficacy of a T-cell directed immunotoxin containing pokeweed antiviral protein (PAP).